1. Field of the Invention
The present invention relates to a novel thermoplastic, biodegradable multi block hydrogel copolymer used for drug delivery matrix, having hydrophobic both end blocks and hydrophilic middle block. More specifically, this invention concerns the thermoplastic, biodegradable hydrogels copolymer which is easily degraded and excreted in human body by the hydrolysis of intramolecular ester and amide bond. The structure of present copolymer comprises i) hydrophilic and swellable soft domain consisting of polyethyleneoxide(PEO), and ii) hydrophobic, biodegradable, crystallizable and non-swellable hard domain consisting of polylactide(PLA), polyglycolide(PGA), polylactideglycolide(PLGA) and polycaprolactone(PCL).
2. Description of the Prior Art
Recently, drug delivery system for regulating the drug release to the specific site within the range of constant effective dose has been researched very actively. For this purpose, biomedical polymers have been developed as drug delivery matrix. However, biomedical polymers developed so far have some drawbacks as follows:
i) It is hard to use biomedical polymers for delivering the drugs having large molecular weight; PA1 ii) Physical treatment is required for removing the non-biodegradable copolymers, if non-biodegradable copolymers are used for drug delivery matrix; and PA1 iii) In case of hydrogels developed up to now, these materials have very low processibility due to their crosslinked nature. Furthermore, these materials cannot be used easily as drug delivery matrix for their toxicity to the human body. PA1 i) copolymers can be easily processed into appropriate preparations by simple processing methods, such as, infusion processing method or solvent casting method, since there is no chemical crosslinkage in copolymers; and PA1 ii) copolymers can be easily degraded into small and nontoxic moleculars by simple hydrolysis or enzyme hydrolysis in order to be easily excreted through kidney. PA1 i) it is hard to be excreted from human body, and PA1 ii) the toxic materials like pentaerythrol are contained to these copolymers. PA1 B(--) shows hydrophobic, biodegradable, crystallizable, and non-swellable polymers essentially consisting of polylactide(PLA), polyglycol ide (PGA), copolymer of PLA/PGA, polycaprolactone, polyorthoester and/or polyanhydride; PA1 X shows the biodegradable chemical 1 inkage, such as, amide linkage, ester linkage, carbamate linkage and carbonate linkage; PA1 Y shows the chemical linkage to link between block (A) and block (B), or block (B) and block (B), such as, amide linkage, ester linkage, carbamate linkage and carbonate linkage; PA1 n shows the integer 0 to 20. PA1 A shows hydrophilic multi-block copolymer as--[--(OCH.sub.2 CH.sub.2).sub.n --X].sub.k --(CH.sub.2 CH.sub.2 O).sub.n --; PA1 X shows --O(CO CH.sub.2 O).sub.x --, --O [COCH(CH.sub.3)O ].sub.x --, --OCH.sub.2 CONH--, --OCH.sub.2 CH.sub.2 CONH--, or --OCONH--; PA1 Y shows --CHyNHCO--; PA1 Y' shows --CONHCHy--; PA1 R.sub.1 and R.sub.2 shows each independently hydrogen or methyl; PA1 x shows the integer 1 to 10; PA1 z shows the integer 1 to 5; PA1 y shows tile integer 0, 1 or 2; PA1 l shows the integer 1, 2 or 3; PA1 m shows the integer 20 to 500; PA1 n shows the integer 20 to 500; and PA1 k shows the integer 0 to 50. The weight of the PEO block lies between five (5) and ninety five (95) percent (w/w) of the multiblock copolymer.
To solve the above mentioned drawbacks, the inventors has researched thermoplastic, biodegradable copolymers having the following properties:
Biodegradable copolymers disclosed so far are aliphatic polyester, polyorthoester, polyanhydride, poly .alpha.-amino acid, polyphosphagen, polyalkylcyanoacrylate. Among the aliphatic polyesters, polylactide(PLA), polyglycolide (PGA) and polylactideglycolide (PLGA) have been approved as the nontoxic copolymers to human by the FDA. These copolymers have been applied as drug delivery devices to carry the drugs having small molecular weight.
Recently, polypetides or proteins produced by cell engineering or recombinant DNA technology have been approved as major medicines. However, these medicines have been administered only by injection, because these medicines are water-soluble and very unstable macromolecular compounds with short half-life. Therefore, finding another suitable delivery route of these compounds becomes a major research subject.
The application of aliphatic polyesters as delivery system of protein drugs has some handicaps owing to their difficulties in loading process, complicated release mechanism, low degradability and their hydrophobic property. Therefore, the improved degradable materials have been required as drug delivery matrix for protein drugs.
Block copolymers as drug delivery matrix were disclosed by U.S. Pat. No. 4,942,035. These copolymers are block copolymers in the shape of PLA/PEO/PLA or PGA/PEO/PGA which comprise polyethyleneoxide as hydrophilic block and polylactide(D-, L- or DL-form), polyglycolide, poly-.epsilon.-caprolactone or poly-3-hydroxybutylic acid as hydrophobic block. However, these block copolymers have some drawbacks as follows:
On the other hand, diblock and triblock copolymers having polyalkyleneoxide and trimethylene carbonate were disclosed by U.S. Pat. No. 4, 716,203. These block copolymers were invented for coating materials, and contained some materials which are not easily degraded and toxic to human body.
Other block copolymers having polyethylene glycol as hydrophilic component and polylactide as hydrophobic component were reported in J. Pol. Sci. (A): Vol. 27,2151(1989) and J. Pol. Sci. (A): Vol. 39 (1990). However, these copolymers were prepared by simple copolymerization of the two components to be used as drug delivery matrix.